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USP 38 Physical Tests / 905 Uniformity of Dosage Units 675

The lowering of the freezing point in dilute solutions by molecules of nearly equal size is expressed by a modified van't Hoff
equation:

in which T = absolute temperature in kelvins; X2 = mole fraction of minor component (solute, impurity); DHf = molar heat of
fusion of the major component in Joules per mol: R = gas constant in Joules per mol kelvins; and KD = distribution ratio of
solute between the solid and liquid phases.
Assuming that the temperature range is small and that no solid solutions are formed (KD = 0).
Integration of the van't Hoff equation yields the following relationship between the mole fraction of impurity and the melt-
ing-point depression:

in which To = melting point of the pure compound, in kelvins, and Tm = melting point of the test specimen, in kelvins.
With no solid solution formation, the concentration of impurity in the liquid phase at any temperature during the melting is
inversely proportional to the fraction melted at that temperature, and the melting-point depression is directly proportional to
the mole fraction of impurity. A plot of the observed test specimen temperature, Ts, versus the reciprocal of the fraction mel-
ted, 1/F, at temperature Ts, should yield a straight line with the slope equal to the melting-point depression (To Tm). The

General Chapters
theoretical melting point of the pure compound is obtained by extrapolation to 1/F = 0:

Substituting the experimentally obtained values for To Tm, DHf, and To in equation (2) yields the mole fraction of the total
eutectic impurity, which, when multiplied by 100, gives the mole percentage of total eutectic impurities.
Deviations from the theoretical linear plot also may be due to solid solution formation (KD 0), so that care must be taken in
interpreting the data.
To observe the linear effect of the impurity concentration on the melting-point depression, the impurity must be soluble in
the liquid phase or melt of the compound, but insoluble in the solid phase, i.e., no solid solutions are formed. Some chemical
similarities are necessary for solubility in the melt. For example, the presence of ionic compounds in neutral organic com-
pounds and the occurrence of thermal decomposition may not be reflected in purity estimates. The extent of these theoretical
limitations has been only partially explored.
Impurities present from the synthetic route often are similar to the end product, hence there usually is no problem of solubil-
ity in the melt. Impurities consisting of molecules of the same shape, size, and character as those of the major component can
fit into the matrix of the major component without disruption of the lattice, forming solid solutions or inclusions; such impuri-
ties are not detectable by DSC. Purity estimates are too high in such cases. This is more common with less-ordered crystals as
indicated by low heats of fusion.
In addition, the method is reliable when the purity of the major component is greater than 98.5 mol% and the materials are
not decomposed during the melting phase.
Impurity levels calculated from thermograms are reproducible and generally reliable within 0.1% for ideal compounds.
Compounds that exist in polymorphic form cannot be used in purity determination unless the compound is completely con-
verted to one form. On the other hand, DSC and DTA are inherently useful for detecting, and therefore monitoring, polymor-
phism.
ProcedureThe actual procedure and the calculations to be employed for eutectic impurity analysis are dependent on the
particular instrument used. Consult the manufacturer's literature and/or the thermal analysis literature for the most appropriate
technique for a given instrument. In any event, it is imperative to keep in mind the limitations of solid solution formation, in-
solubility in the melt, polymorphism, and decomposition during the analysis.

905 UNIFORMITY OF DOSAGE UNITS

This general chapter is harmonized with the corresponding texts of the European Pharmacopoeia and the Japanese Pharmaco-
poeia. Portions of the general chapter text that are national USP text, and are not part of the harmonized text, are marked with
symbols () to specify this fact.
NOTEIn this chapter, unit and dosage unit are synonymous.

To ensure the consistency of dosage units, each unit in a batch should have a drug substance content within a narrow range
around the label claim. Dosage units are defined as dosage forms containing a single dose or a part of a dose of drug sub-

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676 905 Uniformity of Dosage Units / Physical Tests USP 38

stance in each unit. The uniformity of dosage units specification is not intended to apply to suspensions, emulsions, or gels in
unit-dose containers intended for external, cutaneous administration.
The term uniformity of dosage unit is defined as the degree of uniformity in the amount of the drug substance among
dosage units. Therefore, the requirements of this chapter apply to each drug substance being comprised in dosage units con-
taining one or more drug substances, unless otherwise specified elsewhere in this Pharmacopeia.
The uniformity of dosage units can be demonstrated by either of two methods, Content Uniformity or Weight Variation (see
Table 1). The test for Content Uniformity of preparations presented in dosage units is based on the assay of the individual con-
tent of drug substance(s) in a number of dosage units to determine whether the individual content is within the limits set. The
Content Uniformity method may be applied in all cases.
The test for Weight Variation is applicable for the following dosage forms:
(W1) Solutions enclosed in unit-dose containers and into soft capsules;
Solids (including powders, granules, and sterile solids) that are packaged in single-unit containers and contain no active or inactive
(W2)
added substances;
Solids (including sterile solids) that are packaged in single-unit containers, with or without active or inactive added substances, that
(W3) have been prepared from true solutions and freeze-dried in the final containers and are labeled to indicate this method of prepara-
tion; and
Hard capsules, uncoated tablets, or film-coated tablets, containing 25 mg or more of a drug substance comprising 25% or more,
(W4) by weight, of the dosage unit or, in the case of hard capsules, the capsule contents, except that uniformity of other drug substan-
ces present in lesser proportions is demonstrated by meeting the requirements for Content Uniformity.

The test for Content Uniformity is required for all dosage forms not meeting the above conditions for the Weight Variation
General Chapters

test.1
Table 1. Application of Content Uniformity (CU) and Weight Variation (WV) Tests for Dosage Forms
Dose & Ratio of
Drug Substance
25 mg and <25 mg or
Dosage Form Type Subtype 25% <25%
Uncoated WV CU
Tablets Film WV CU
Coated
Others CU CU
Hard WV CU
Suspension, emulsion,
Capsules
Soft or gel CU CU
Solutions WV WV
Single component WV WV
Solution freeze-dried in final
Solids in single-unit containers
Multiple components container WV WV
Others CU CU
Solutions in unit-dose
containers and into soft capsules WV WV
Others CU CU

CONTENT UNIFORMITY

Select not fewer than 30 units, and proceed as follows for the dosage form designated.
Where different procedures are used for assay of the preparation and for the Content Uniformity test, it may be necessary to
establish a correction factor to be applied to the results of the latter.

Solid Dosage Forms

Assay 10 units individually using an appropriate analytical method. Calculate the acceptance value (see Table 2).

1 European Pharmacopoeia and Japanese Pharmacopoeia text not accepted by the United States Pharmacopeia: Alternatively, products listed in item (4) above
that do not meet the 25 mg/25% threshold limit may be tested for uniformity of dosage units by Mass Variation instead of the Content Uniformity test if the
concentration relative standard deviation (RSD) of the drug substance in the final dosage units is not more than 2%, based on process validation data and develop-
ment data, and if there has been regulatory approval of such a change. The concentration RSD is the RSD of the concentration per dosage unit (w/w or w/v),
where concentration per dosage unit equals the assay result per dosage unit divided by the individual dosage unit weight. See the RSD formula in Table 2.

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USP 38 Physical Tests / 905 Uniformity of Dosage Units 677

Liquid or Semi-Solid Dosage Forms

Assay 10 units individually using an appropriate analytical method. Carry out the assay on the amount of well-mixed materi-
al that is removed from an individual container in conditions of normal use, and express the results as delivered dose. Calculate
the acceptance value (see Table 2).

Calculation of Acceptance Value

Calculate the acceptance value by the formula:

in which the terms are as defined in Table 2.


Table 2
Variable Definition Conditions Value
Mean of individual contents (c1, c2,
, cn), expressed as a percentage
X of the label claim
c1, c2, , cn Individual contents of the units tes-
ted, expressed as a percentage of

General Chapters
the label claim
n Sample size (number of units in a
sample)
k Acceptability constant If n = 10, then k = 2.4
If n = 30, then k = 2.0
s Sample standard deviation

RSD Relative standard deviation (the 100s/X


sample standard deviation ex-
pressed as a percentage of the
mean)
M (case 1) to be applied when Reference value If 98.5% X 101.5%, then M = X (AV = ks)
T 101.5 M = 98.5%
If X <98.5%, then (AV = 98.5 X + ks)
M = 101.5%
If X >101.5%, then (AV = X 101.5 + ks)
M (case 2) to be applied when Reference value M=X
If 98.5 X T, then
T >101.5 (AV = ks)
M = 98.5%
If X <98.5%, then (AV = 98.5 X + ks)
M = T%
If X >T, then (AV = X T + ks)
Acceptance value (AV) General formula:

(Calculations are specified above for


the different cases.)
L1 Maximum allowed acceptance value L1 = 15.0 unless otherwise specified
L2 Maximum allowed range for devia- On the low side, no dosage unit L2 = 25.0 unless otherwise specified
tion of each dosage unit tested result can be less than [1
from the calculated value of M (0.01)(L2)]M, while on the high
side, no dosage unit result can be
greater than [1 + (0.01)
(L2)]M. (This is based on an L2
value of 25.0.)

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678 905 Uniformity of Dosage Units / Physical Tests USP 38

Table 2 (Continued)
Variable Definition Conditions Value
T Target content per dosage unit at
the time of manufacture, expressed
as a percentage of the label claim.
Unless otherwise stated, T is
100.0%, or T is the manufacturer's
approved target content per dos-
age unit.

WEIGHT VARIATION

Carry out an assay for the drug substance(s) on a representative sample of the batch using an appropriate analytical meth-
od. This value is result A, expressed as percentage of label claim (see Calculation of Acceptance Value). Assume that the concen-
tration (weight of drug substance per weight of dosage unit) is uniform. Select not fewer than 30 dosage units, and proceed
as follows for the dosage form designated.

Uncoated or Film-Coated Tablets

Accurately weigh 10 tablets individually. Calculate the content, expressed as percentage of label claim, of each tablet from
General Chapters

the weight of the individual tablet and the result of the Assay. Calculate the acceptance value.

Hard Capsules

Accurately weigh 10 capsules individually, taking care to preserve the identity of each capsule. Remove the contents of each
capsule by a suitable means. Accurately weigh the emptied shells individually, and calculate for each capsule the net weight
of its contents by subtracting the weight of the shell from the respective gross weight. Calculate the drug substance content
of each capsule from the net weight of the individual capsule content and the result of the Assay. Calculate the acceptance
value.

Soft Capsules

Accurately weigh 10 intact capsules individually to obtain their gross weights, taking care to preserve the identity of each
capsule. Then cut open the capsules by means of a suitable clean, dry cutting instrument such as scissors or a sharp open
blade, and remove the contents by washing with a suitable solvent. Allow the occluded solvent to evaporate from the shells at
room temperature over a period of about 30 minutes, taking precautions to avoid uptake or loss of moisture. Weigh the indi-
vidual shells, and calculate the net contents. Calculate the drug substance content in each capsule from the weight of prod-
uct removed from the individual capsules and the result of the Assay. Calculate the acceptance value.

Solid Dosage Forms Other Than Tablets and Capsules

Proceed as directed for Hard Capsules, treating each unit as described therein. Calculate the acceptance value.

Liquid Dosage Forms

Accurately weigh the amount of liquid that is removed from each of 10 individual containers in conditions of normal use. If
necessary, compute the equivalent volume after determining the density. Calculate the drug substance content in each con-
tainer from the mass of product removed from the individual containers and the result of the Assay. Calculate the acceptance
value.

Calculation of Acceptance Value

Calculate the acceptance value as shown in Content Uniformity, except that the individual contents of the units are replaced
with the individual estimated contents defined below.
c1, c2, , cn = individual estimated contents of the units tested, where ci = wi A/W
w1, w2, , wn = individual weights of the units tested
A = content of drug substance (% of label claim) obtained using an appropriate analytical method
W = mean of individual weights
(w1, w2, , wn)

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USP 38 Physical Tests / 911 ViscosityCapillary Methods 679

CRITERIA

Apply the following criteria, unless otherwise specified.

Solid, Semi-Solid, and Liquid Dosage Forms

The requirements for dosage uniformity are met if the acceptance value of the first 10 dosage units is less than or equal to
L1%. If the acceptance value is > L1%, test the next 20 units, and calculate the acceptance value. The requirements are met if
the final acceptance value of the 30 dosage units is L1%, and no individual content of any dosage unit is less than [1
(0.01)(L2)]M nor more than [1 + (0.01)(L2)]M as specified in the Calculation of Acceptance Value under Content Uniformity or
under Weight Variation. Unless otherwise specified, L1 is 15.0 and L2 is 25.0.

Change to read:

911 VISCOSITYCAPILLARY
USP38 METHODS
Change to read:
The following procedures are used to determine the viscosity of a Newtonian fluid, i.e., a fluid having a viscosity that is inde-
pendent of the rate of shear. [NOTEFor additional information, see Rheometry 1911.]USP38

General Chapters
Change to read:

METHOD I. SUSPENDED-LEVEL (OR UBBELOHDE-TYPE)USP38 CAPILLARY VISCOMETER


Apparatus: The determination may be carried out with a suspended-levelUSP38 capillary viscometer (Figure 1). USP38

Figure 1. Suspended-level (or Ubbelohde-type)USP38 capillary viscometer.

Other viscometers may be used provided that the accuracy and precision is NLT that obtained with the viscometers de-
scribed in this chapter.USP38
Procedure: Fill the viscometer through tube (L) with a sufficient quantity of the sample liquid that is appropriate for the
viscometer being used or by following the manufacturers instructions. Carry out the experiment with the tube in a vertical
position. Fill bulb (A) with the liquid, and also ensure that the level of liquid in bulb (B) is below the exit to the ventilation
tube (M). Immerse the viscometer in a water or oil bath stabilized at the temperature specified in the individual mono-

Official from August 1, 2015


Copyright (c) 2015 The United States Pharmacopeial Convention. All rights reserved.